title: Infarct-size limitation by preconditioning is enhanced by dipyridamole administered before but not after preconditioning: evidence for the role of interstitial adenosine level during preconditioning as a primary determinant of cardioprotection.
abstract: Although the importance of adenosine (Ado)-receptor activation in preconditioning (PC) has been established, it is unclear whether cardioprotection afforded by PC is determined by the Ado level during PC ischemia or by that during sustained ischemia. Accordingly, we tested whether the PC effect is modified by augmenting the increase in the interstitial Ado level during PC or by that during sustained ischemia. In the first series of experiments, the effect of 0.25 mg/kg dipyridamole (DIP) on the interstitial Ado level was assessed by in vivo microdialysis in the rabbit heart. Dialysate Ado during 2-min ischemia was 70% higher in the heart pretreated with 0.25 mg/kg of DIP than in the untreated controls, indicating that DIP was capable of enhancing an ischemia-induced increase of interstitial Ado. In the second series of experiments, myocardial infarction was induced in the rabbit by 30-min coronary artery occlusion and 3-h reperfusion. Infarct size was determined by tetrazolium staining and expressed as percentage of area at risk (%IS/AR). Rabbits were subjected to one of nine treatments before the 30-min ischemia: no treatment, DIP (0.25 mg/kg, i.v.), PC with 2-min ischemia, DIP before 2-min PC, DIP after 2-min PC, PC with 3-min ischemia, DIP before 3-min PC, DIP after 3-min PC, or 8-sulfophenyltheophylline (SPT) after 3-min PC. DIP alone did not modify %IS/AR (38.8 +/- 5.8% vs. 41.2 +/- 4.7%), but administration of DIP before 2-min PC significantly enhanced the infarct size-limiting effect (14.6 +/- 2.1% with DIP vs. 32.1 +/- 4.7% without DIP). Although the 3-min PC per se could achieve significant infarct limitation, the effect of DIP on 3-min PC was not significant (14.7 +/- 1.9% with DIP vs. 20.5 +/- 1.8% without DIP). On the other hand, the effect of DIP administered after PC was very slight (only 7% reduction of %IS/AR) and statistically insignificant, regardless of the duration of PC ischemia. However, infarct limitation by 3-min PC was inhibited by SPT given after the PC (%IS/AR = 34.5 +/- 3.2), as reported previously. These results suggest that the interstitial Ado level during PC ischemia, not the level during sustained ischemia, is a primary determinant of the extent of cardioprotection by PC and that the threshold for Ado-receptor activation required during sustained ischemia is much lower than that for triggering PC.
authors.affiliation: Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: T
authors.initials: T
authors.lastname: Miura
authors.forename: T
authors.initials: T
authors.lastname: Miki
authors.forename: A
authors.initials: A
authors.lastname: Tsuchida
authors.forename: K
authors.initials: K
authors.lastname: Shimamoto
mesh_terms: D000241:Adenosine / Q000032:analysis / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D004176:Dipyridamole / Q000008:administration & dosage / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011687:Purines / Q000378:metabolism; D011817:Rabbits; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D011687:Purines; D014665:Vasodilator Agents; D004176:Dipyridamole; D000241:Adenosine